EP2132179B1 - Process for preparing isomers of carmoterol - Google Patents

Process for preparing isomers of carmoterol Download PDF

Info

Publication number
EP2132179B1
EP2132179B1 EP08709552A EP08709552A EP2132179B1 EP 2132179 B1 EP2132179 B1 EP 2132179B1 EP 08709552 A EP08709552 A EP 08709552A EP 08709552 A EP08709552 A EP 08709552A EP 2132179 B1 EP2132179 B1 EP 2132179B1
Authority
EP
European Patent Office
Prior art keywords
compound
acid
formula
process according
diastereomer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP08709552A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP2132179A1 (en
Inventor
Rajendra Narayanrao Kankan
Dharmaraj Ramachandra Rao
Dilip Birari
Ashwini Amol Sawant
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cipla Ltd
Original Assignee
Cipla Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cipla Ltd filed Critical Cipla Ltd
Publication of EP2132179A1 publication Critical patent/EP2132179A1/en
Application granted granted Critical
Publication of EP2132179B1 publication Critical patent/EP2132179B1/en
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to a novel process for the synthesis of R,R-Carmoterol.
  • WO 95/25104 also relates to a process for preparing (R)-8-benzyloxy-5-oxyranylcarbostyril, an intermediate of carmoterol, and there is no disclosure of a process for preparing carmoterol itself.
  • a compound of formula (III) of WO95/25104 is reacted with the (R)-8-benzyloxy-5-oxiranylcarbostyril) compound (II) to form a protected precursor to a carmoterol derivative.
  • the compound (III) is in the form of a free amine.
  • a disadvantage of the process for preparing the carmoterol derivative is that the use of free amine in excess gives rise to dimeric impurities as well as regioisomers which are difficult to separate.
  • the dimeric impurity of a precursor to carmoterol would have the following structure.
  • the present invention provides a process for synthesis of carmoterol which avoids all the disadvantages associated with prior art.
  • Another object of the present invention is to provide novel intermediates for the synthesis of (R,R)-carmoterol.
  • Yet another object of the present invention is to provide an improved process for preparing the novel intermediates used in the synthesis of (R,R)-carmoterol.
  • Yet another object of the present invention is to provide a process which is simple, economical and suitable for industrial scale up.
  • R 1 is a group selected from alkyl, aryl, allyl, alkoxy, cycloalkyl, heterocyclic, alkenyl, benzocycloalkyl, aralkyl, haloarylalkyl, heteroaralkyl, haloalkyl, alkoxyaralkyl, and optionally substituted silyl; and either (a) R 2 and R 2' are trialkylsilyl and R 3 is hydrogen; (b) R 2 and R 3 are trialkylsilyl and R 2'
  • the (R,R)-diastereomer of compound (III) is prepared by reacting the R enantiomer of compound (I) with the R enantiomer of compound (II).
  • the (R,S)-diastereomer of compound (III) is prepared by reacting the R enantiomer of compound (I) with the S enantiomer of compound (II).
  • the (S,S)-diastereomer of compound (III) is prepared by reacting the S enantiomer of compound (I) with the S enantiomer of compound (II).
  • the (S,R)-diastereomer of compound (III) is prepared by reacting the S enantiomer of compound (I) with the R enantiomer of compound (II).
  • R 1 is straight chain or branched alkyl, for example, C 1 -C 10 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight- or branched-pentyl, straight- or branched-hexyl, straight- or branched-heptyl, straight- or branched-nonyl or straight- or branched-decyl.
  • alkyl is C 1 -C 4 alkyl.
  • R 1 is C 6 -C 14 aryl, preferably C 6 -C 10 aryl.
  • the aryl group may be substituted by at least one group selected from mercapto, dialkylamino, nitro, alkoxy, halogen, keto, cyano or a combination.
  • aryl is benzyl.
  • alkoxy means “alkyloxy", wherein “alkyl” has the same meanings as given above.
  • R 1 is straight chain or branched alkoxy, for example C 1 -C 10 alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy or straight-or branched-pentoxy, -hexyloxy, -heptyloxy, -octyloxy, -nonyloxy or - decyloxy.
  • R1 is C 1 -C 4 alkoxy.
  • R 1 is a monovalent heterocyclic group having up to 20 carbon atoms and one, two, three or four heteroatoms selected from nitrogen, oxygen and sulfur, the group optionally having an alkyl, alkylcarbonyl, hydroxyalkyl, alkoxyalkyl or aralkyl group attached to a ring carbon or nitrogen atom and being linked to the remainder of the molecule through a ring carbon atom, for example a group, preferably a monocyclic group, with one nitrogen, oxygen or sulfur atom, such as pyrryl, pyridyl, piperidyl, furyl, tetrahydrofuryl or thienyl, or a group, preferably a monocyclic group, with two hetero atoms selected from nitrogen, oxygen and sulfur, such as imidazolyl, pyrimidinyl, piperazinyl, oxazolyl, isoxazolyl, thiazolyl, morpholinyl or thiomorpholinyl.
  • heterocyclic is a monocyclic group having 5-or 6-ring atoms and one or two nitrogen atoms, or one nitrogen atom and one oxygen atom, in the ring and optionally substituted on a ring nitrogen atom by C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl or phenyl C 1 -C 4 alkyl.
  • R 1 is straight chain or branched-alkenyl, for example C 2 -C 10 alkenyl, for example vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, or straight- or branched-pentenyl, -hexenyl, -heptenyl, -octenyl, -nonenyl or -decenyl.
  • R 1 is C 2 -C 4 alkenyl.
  • R 1 is benzocycloalkyl wherein cycloalkyl is as defined above, attached at two adjacent carbon atoms to a benzene ring.
  • R 1 is benzo-C 5 -C 6 -cycloalkyl, or benzocyclohexyl (tetrahydronaphthyl).
  • R 1 is aralkyl meaning arylalkyl, wherein aryl and alkyl have the same meanings as given above, such as straight- or branched- chain C 6 -C 10 aryl-C 1 -C 10 alkyl, for example one of the C 1 -C 10 alkyl groups mentioned above, particularly one of the C 1 -C 4 alkyl groups, substituted by phenyl, tolyl, xylyl or naphthyl.
  • aralkyl is phenyl-C 1 -C 4 alkyl, particularly benzyl or 2-phenylethyl.
  • R 1 is haloarylalkyl wherein aralkyl is as defined above, substituted by one or more heterocyclic groups as defined above.
  • R 1 is heteroaralkyl wherein aralkyl is as defined above wherein one, two, three or four carbon atoms are replaced with heteroatoms selected from nitrogen, oxygen and sulfur.
  • R 1 is alkoxyaralkyl wherein alkoxy and aralkyl have the same definitions as given above.
  • R 1 is substituted silyl group wherein the silyl group is substituted with at least one alkyl group as defined above.
  • the salt of compound (II) is the hydrochloride salt.
  • R 2 and R 2 ' are trialkylsilyl, wherein alkyl has the same meanings as given above and each alkyl may be the same or different.
  • the silyl group is selected from the group consisting of trimethylsilyl, triethylsilyl and t-butyldimethylsilyl.
  • R 2 may be diarylalkylsilyl, wherein aryl and alkyl have the same meanings as given above and each aryl may be the same or different.
  • the diarylalkylsilyl is t-butyldiphenylsilyl.
  • R 2 and R 3 are trialkylsilyl, wherein alkyl has the same meanings as given above and each alkyl may be the same or different.
  • the silyl group is selected from the group consisting of trimethylsilyl, triethylsilyl and t-butyldimethylsilyl.
  • R 3 may be diarylalkylsilyl, wherein aryl and alkyl have the same meanings as given above and each aryl may be the same or different.
  • the diarylalkylsilyl is t-butyldiphenylsilyl.
  • the condensation is carried out in the presence of a solvent.
  • the solvent may be an organic solvent, for example the organic solvent may be selected from the group consisting of methanol, ethanol, isopropyl alcohol (IPA), t-butanol, methyl isobutylketone, toluene, t-amylalcohol, acetonitrile, diglyme, dimethylsulphoxide (DMSO) xylene and hexamethylphosphoramide (HMPA).
  • the condensation may be carried out in the absence of solvent. In this embodiment, the condensation is suitably carried out at a temperature ranging from about 100 to about 140°C.
  • the condensation step is carried out below 140°C, suitably below 120°C.
  • the condensation step is carried out in the presence of a base.
  • the base may be an organic base or an inorganic base.
  • the base may be selected from triethylamine, potassium carbonate, sodium carbonate and diisopropylethylamine.
  • R 2 is trialkylsilyl or diarylalkylsilyl and the compound of formula (II) is designated (IIa). It has surprisingly been found that the use of the silylated compound of formula (IIa) minimizes the formation of the dimeric impurity and regioisomer.
  • the compound of formula (IIa) may be obtained by reacting the compound of formula (II) wherein R 2 is hydrogen (designated compound (IIc)) with a suitable silylating agent.
  • the silylating agent comprises a silyl group and may comprise a trialkylsilyl group, wherein the term "trialkylsilyl” has the same meaning as given above.
  • the silylating agent may comprise a diarylalkylsilyl group, wherein the term "diarylalkylsilyl” has the same meaning as given above.
  • the silyl group is selected from the group consisting of trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl and t-butyldimethylsilyl.
  • the compound of formula (IIc) can be made by any process known in the art, for example as described in US 4,579,854 .
  • the compound of formula (IIa) is condensed with the compound of formula (I) wherein R 1 is benzyl, optionally at about 110°C, to give the corresponding compound of formula (III).
  • the condensation step is carried out in a solvent, preferably HMPA, which minimizes the formation of the dimeric impurity and regioisomer.
  • the reaction is carried out using HMPA solvent preferably at a temperature below 100°C. It has surprisingly been found that these reaction conditions minimize the formation of the dimeric impurity and regioisomer.
  • compound (Ig) is prepared by converting a compound of formula (If) to the compound (Ig).
  • the conversion may be according to any process described in this specification.
  • compound (If) is prepared by converting a compound of formula (Ie) to the compound (If).
  • the conversion may be according to any process described in this specification.
  • compound (Ie) is prepared by converting a compound of formula (Id) to the compound (Ie).
  • the conversion may be according to any process described in this specification.
  • the condensation and hydrolyzation steps may be carried out without isolation of the compound (III).
  • the (R,R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of the compound of formula (IV) or (V) is converted to the corresponding (R,R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of carmoterol.
  • the conversion comprises deprotection of the OR 1 group using a suitable deprotecting reagent.
  • the deprotection reagent depends on the nature of the protecting group.
  • the hydrolyzation and deprotection steps may be carried out without isolation of the compound (IV) or (V).
  • the condensation, hydrolyzation and deprotection steps may be carried out without isolation of the compounds (III) and (IV) or (V).
  • the deprotection may comprise hydrogenolysis of the compound of formula (IV) or (V) in the presence of a noble metal catalyst and hydrogen gas.
  • deprotecting reagents such as mineral acids, strong acids, Lewis acids or aqueous mineral bases in a suitable solvent.
  • the deprotection of compound (IV) or (V) is carried out in the presence of a solvent.
  • the solvent may be selected from an organic solvent such as an alkyl acetate, lower alkylamines for example C 1 to C 6 alkylamines, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, heterocycles or dialkylethers, an acid, a mixture of water and a water miscible solvent, ionic liquids, halogenated solvents and mixtures thereof.
  • the R,R-carmoterol base is converted to a pharmaceutically acceptable salt thereof.
  • a process for preparing the (R,R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of carmoterol comprising converting the corresponding (R,R)-, (S,S)-, (R,S)- or (S,R)-diastereomer of a compound of formula (III) to the compound of formula (V) in the presence of an acid having the formula HA, wherein R 1 , R 2 , R 2 ', R 3 and A - have the same meanings as given above.
  • the (R,R)-diastereomer of the compound of formula (III) is converted to (R,R)-carmoterol.
  • compound of formula (II) is in the form of the R enantiomer.
  • R 2 is a trialkylsilyl group, wherein the term "alkyl" has the same meaning as given above and each alkyl may be the same or different.
  • the trialkylsilyl group is selected from the group consisting of trimethylsilyl, triethylsilyl and t-butyldimethylsilyl.
  • R 2 may be diarylalkylsilyl, wherein aryl and alkyl have the same meanings as given above and each aryl may be the same or different.
  • the diarylalkylsilyl is t-butyldiphenylsilyl.
  • compound of formula (II) is in the form of the R enantiomer.
  • the silylating agent may be hexamethyldisilazane (to form compound (II) wherein R 2 is triethylsilyl) or hexaethyldisilazane (to form compound (II) wherein R 2 is triethylsilyl).
  • the (R)-N-(2-(p-methoxyphenyl)-1-methylethyl)amine may be made by any process known in the art, for example as described in US 4,579,854 .
  • the (R)-N-(2-(p-methoxyphenyl)-1-methylethyl)amine may be prepared by resolving 4-methoxyphenylacetone using R-(+)-phenyl ethyl amine in the presence of a first reducing agent to produce (R)-(+)-N-(1-phenylethyl)-N-[1-(p-methoxyphenyl)-2-propyl)]amine, optionally converting the (R)-(+)-N-(1-phenylethyl)-N-[1-(p-methoxyphenyl)-2-propyl)]amine hydrochloride to a salt such as the hydrochloride salt, followed by converting the (R)-(+)-N-(1-phenylethyl)-N-[1-(p-methoxyphenyl)-2-propyl)]amine or salt thereof to the (R)-N-(2-(p-methoxy
  • the second reducing agent is 10% palladium on carbon and methanol.
  • the R enantiomer of the compound of formula (I) is prepared by subjecting the compound of formula (If) to chiral reduction to form the R enantiomer of the compound of formula (Ig) followed by cyclisation to the R enantiomer of the compound of formula (I).
  • the S enantiomer of the compound of formula (I) is prepared by subjecting the compound of formula (If) to chiral reduction to form the S enantiomer of the compound of formula (Ig) followed by cyclisation to the S enantiomer of the compound of formula (I).
  • the bromoacetyl compound (If) is subjected to chiral reduction using a chiral reducing agent selected from the group consisting of (-)-DIP-chloride, ⁇ -isopinocamphinyl-9BBN (R-Alpine-Borane), a chiral ⁇ -oxoaldiminatocobalt (II) complex and a borane reducing agent, and optionally in the presence of a catalytic amount of a single enantiomer of an oxazaborolidine derived from a chiral oxazaborolidine catalyst.
  • a chiral reducing agent selected from the group consisting of (-)-DIP-chloride, ⁇ -isopinocamphinyl-9BBN (R-Alpine-Borane), a chiral ⁇ -oxoaldiminatocobalt (II) complex and a borane reducing agent, and optionally in the presence of a cat
  • the chiral reducing agent is a chiral ⁇ -oxoaldiminatocobalt (II) complex, and the complex is present in an amount of about 1 mol%.
  • the compound of formula (I) is obtained without isolation of the compound of formula (Ig).
  • the compound of formula (If) is prepared by brominating a compound of formula (Ie) in the presence of a brominating agent wherein R 1 has the same meanings as given above.
  • a process for preparing a compound of formula (Ie) comprising heating a compound of formula (Id) in the presence of a reagent wherein R 1 has the same meanings as given above and the reagent is present in a volume ranging from about 1.5 volumes to about 5 volumes.
  • a “volume” refers to the volume of the solvent (in ml) used per gram of the compound being dissolved.
  • the reagent is present in a volume ranging from about 1.5 volumes to about 3 volumes, preferably 2 volumes.
  • the compound of formula (Ie) used to prepare the compound of formula (If) as described above is prepared according to the process described above.
  • a process for preparing a compound of formula (Id) comprising oxidising a compound of formula (Ic) in the presence of an oxidizing agent and a solvent selected from dichloromethane, ethyl acetate or a mixture thereof wherein R 1 has the same meanings as given above.
  • the oxidizing agent is selected from the group consisting of: peracids such as peroxybenzoic acid, m-chloroperbenzoic acid, peracetic acid, peroxytrifluoroacetic acid, peroxysulfuric acid, perboric acid, performic acid, peroxymaleic acid and peroxydichloromaleic acid (for example, prepared from hydrogen peroxide and dichloromaleic anhydride); tert-butyl hydroperoxide in the presence of a vanadium catalyst; dimethyl dioxirane; selenium dioxide; m-phenanthroline di-N-oxide (for example prepared from H 2 O 2 and m-phenanthroline); nitric acid and hydrogen peroxide.
  • the oxidizing agent is m-chloroperoxybenzoic acid.
  • the process for preparing compound (Id) is carried out for a period of time less than 10 hours, preferably less than 8 hours, more preferably less than 6 hours.
  • the compound of formula (Id) used to prepare the compound of formula (Ie) as described above is prepared according to the process described above.
  • a process for preparing a compound of formula (Ic) comprising reacting a compound of formula (Ib) with a protecting group in the presence of a low boiling point solvent wherein R 1 has the same meanings as given above.
  • the low boiling solvent may have a boiling point below 70°C, , preferably below 60°C.
  • the solvent is acetone.
  • Suitable protecting groups for hydroxy groups are well known to those skilled in the art and include a compound comprising a group selected from lower alkanoyl for example a C 1 to C 6 alkanoyl, substituted or unsubstituted benzyl and substituted or unsubstituted phenyl.
  • the protecting agent is benzyl bromide and this results in the work up procedure being simplified by distillation, avoiding any extraction procedure.
  • the compound of formula (Ic) used to prepare the compound of formula (Id) as described above is prepared according to the process described above.
  • the solvent used for the above process of invention is advantageous over solvents used in the prior art (for example, Journal of American Chemical Society 1930, Vol 52, pp 4433-4436 , which uses nitrobenzene) in that the latter are high-boiling point, hazardous solvents that require steam distillation to be removed, in order to isolate the product.
  • the product of the process of the present invention is easily isolated, for example by quenching the reaction mass in water and optionally converting the product to base.
  • the acylating agent is a haloacetyl compound, wherein halo is chloro, bromo, iodo or fluoro, preferably chloro.
  • the acid catalyst is a Lewis acid catalyst, for example boron trichloride, aluminum chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride or zinc chloride.
  • a Lewis acid catalyst for example boron trichloride, aluminum chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride or zinc chloride.
  • the compound of formula (Ib) used to prepare the compound of formula (Ic) as described above is prepared according to the process described above.
  • (R,R)-carmoterol as described above in the manufacture of a medicament for the treatment of asthma or chronic obstructive pulmonary disease (COPD) is disclosed.
  • the present invention provides an improved process for the synthesis of optically pure carmoterol, more particularly (R,R) and (S,S)-carmoterol.
  • the compound of formula (I) is condensed with the compound of formula (II) in a solvent such as methanol, ethanol, isopropyl alcohol (IPA), t-butanol, methyl isobutylketone, toluene, t-amylalcohol, acetonitrile, diglyme, dimethylsulphoxide (DMSO) xylene or HMPA below 140°C.
  • IPA isopropyl alcohol
  • t-butanol methyl isobutylketone
  • toluene t-amylalcohol
  • acetonitrile diglyme
  • DMSO dimethylsulphoxide
  • HMPA dimethylsulphoxide
  • This reaction can be optionally carried out in the absence of solvent at a temperature ranging from about 100 to about 140°C, to give an optically pure compound (III).
  • this reaction can also be carried out optionally in the presence of, either organic or inorganic base, such as tri
  • Steps (i) and (ii) may be carried out without isolation of the compound (III).
  • the compound of formula (IV) or (V) may be isolated by crystallization. Crystallization helps in eliminating the impurities associated with the reaction, as it reduces the amount of regioisomer formed during the condensation step.
  • the acid addition salt may be converted to a different salt, such as the hydrochloride salt. The conversion of the acid addition salt may either involve isolation of the free base or no isolation of the free base. This conversion further reduces dimeric and regio isomeric impurities below the detection limit.
  • the process of the present invention may further comprise (iii) deprotection of the OR 1 group under suitable deprotecting conditions. As is well known to the skilled person, the deprotection conditions depend on the nature of the protecting group.
  • R 1 is arylalkyl or substituted arylalkyl
  • a preferred method for deprotection is catalytic reduction using catalysts such as palladium, palladium hydroxide, palladium on activated carbon, palladium on alumina, platinum, platinum on activated carbon and Raney nickel.
  • the solvent used in step (iii) is preferably selected from an alkyl acetate, lower alkylamines, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, heterocycles, dialkylethers, an acid, mixture of water and water miscible solvents, ionic liquids, halogenated solvents and mixtures thereof.
  • the process of the present invention may further comprise: (iv) converting R,R-carmoterol base to a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) may be prepared from a bromoacetyl compound of formula (If) as shown in Scheme 2. wherein the bromoacetyl compound is subjected to chiral reduction using chiral reducing agents such as (-)-DIP-chloride, ⁇ -isopinocamphinyl-9BBN (R-Alpine-Borane).
  • chiral reducing agents such as (-)-DIP-chloride, ⁇ -isopinocamphinyl-9BBN (R-Alpine-Borane).
  • the epoxide of formula (I) may be obtained without isolation of the bromohydrin of formula (Ig), preferably in the presence of a base such as piperidine, pyridine or pyrrolidine.
  • the epoxide obtained may be purified by recrystallisation from an inert organic solvent.
  • the catalyst optionally used for the preparation of (Ig), for example the single enantiomer of an oxazaborolidine, may be generated in situ from R-diphenyl prolinol and diborane.
  • the compound of formula (II) may be synthesised in the form of the S enantiomer and the compound of formula (I) may be synthesised in the form of the S enantiomer, and the two S enantiomers reacted in accordance with the process described above to prepare the (S,S) diastereomer of compound (III) followed by conversion to the (S,S) diastereomer of compound (IV) or (V) in accordance with the process described above, then converted to (S,S)-carmoterol in accordance with the process described above.
  • the crude 5-Bromoacetyl-8-benzyloxycarbostyril (56gms) was charged along with chloroform (280 ml) in a round bottom flask.
  • the reaction mass was heated to reflux for 30 minutes, cooled to 25-30°C in 2-3 hours.
  • the reaction mass was further chilled to 0-5°C and stirred for 30 minutes.
  • the resulting solid was isolated by filtration, washed with chloroform (55ml) and dried under vacuum at 55-60°C for 4-5 hours to yield 41 gms of 5-Bromoacetyl-8-benzyloxycarbostyril..

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP08709552A 2007-02-28 2008-02-28 Process for preparing isomers of carmoterol Not-in-force EP2132179B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN391MU2007 2007-02-28
PCT/GB2008/000677 WO2008104781A1 (en) 2007-02-28 2008-02-28 Process for preparing isomers of carmoterol

Publications (2)

Publication Number Publication Date
EP2132179A1 EP2132179A1 (en) 2009-12-16
EP2132179B1 true EP2132179B1 (en) 2012-08-08

Family

ID=39366461

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08709552A Not-in-force EP2132179B1 (en) 2007-02-28 2008-02-28 Process for preparing isomers of carmoterol

Country Status (9)

Country Link
US (1) US8236959B2 (ko)
EP (1) EP2132179B1 (ko)
JP (1) JP2010520188A (ko)
KR (1) KR20090121360A (ko)
AU (1) AU2008220617B2 (ko)
CA (1) CA2679059A1 (ko)
NZ (1) NZ579244A (ko)
WO (1) WO2008104781A1 (ko)
ZA (1) ZA200905996B (ko)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2008220617B2 (en) 2007-02-28 2012-12-06 Cipla Limited Process for preparing isomers of carmoterol
EP2116537A1 (en) * 2008-05-07 2009-11-11 CHIESI FARMACEUTICI S.p.A. Polymorph of 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone monohydrochloride
KR101906630B1 (ko) 2011-06-10 2018-10-10 키에시 파르마슈티시 엣스. 피. 에이. 무스카린 수용체 길항제 및 베타2 아드레날린 수용체 작용제 효능을 갖는 화합물
US10227305B2 (en) * 2014-08-22 2019-03-12 G. Pratap REDDY Process for preparing indacaterol and salts thereof
TWI703138B (zh) 2015-02-12 2020-09-01 義大利商吉斯藥品公司 具有蕈毒鹼受體拮抗劑及β２腎上腺素受體促效劑活性之化合物
CN106334578B (zh) * 2016-07-29 2018-10-23 马鞍山市泰博化工科技有限公司 一种喹啉衍生物、该衍生物的合成方法及其合成用催化剂

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4579857A (en) * 1983-02-14 1986-04-01 Schering Corporation Anti-inflammatory 1-mercaptoalkyl-substituted-2-imidazolidinone derivatives, composition, and method of use therefor
GB8334494D0 (en) * 1983-12-24 1984-02-01 Tanabe Seiyaku Co Carbostyril derivatives
US4894219A (en) * 1988-03-29 1990-01-16 University Of Florida Beta-agonist carbostyril derivatives, assay method and pharmacological composition
JPH0525045A (ja) * 1991-07-18 1993-02-02 Tanabe Seiyaku Co Ltd 経皮吸収製剤
GB9405019D0 (en) 1994-03-15 1994-04-27 Smithkline Beecham Plc Novel compounds
TWI324150B (en) 2003-02-28 2010-05-01 Novartis Ag Process for preparing 5-[(r)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1h)-quinolin-2-one salt
US7307076B2 (en) * 2004-05-13 2007-12-11 Boehringer Ingelheim International Gmbh Beta agonists for the treatment of respiratory diseases
CA2565243A1 (en) * 2004-05-13 2005-11-24 Boehringer Ingelheim International Gmbh Hydroxy-substituted benzo-condensed heterocycles for use as beta agonists in the treatment of respiratory diseases
DE602006010088D1 (de) * 2005-08-01 2009-12-10 Chiesi Farma Spa Pharmazeutische formulierungen mit einem langzeit-beta-2-agonisten zur verabreichung durch verneblung
AU2008220617B2 (en) 2007-02-28 2012-12-06 Cipla Limited Process for preparing isomers of carmoterol

Also Published As

Publication number Publication date
ZA200905996B (en) 2010-05-26
NZ579244A (en) 2012-04-27
KR20090121360A (ko) 2009-11-25
EP2132179A1 (en) 2009-12-16
CA2679059A1 (en) 2008-09-04
WO2008104781A1 (en) 2008-09-04
JP2010520188A (ja) 2010-06-10
US20100113790A1 (en) 2010-05-06
AU2008220617B2 (en) 2012-12-06
AU2008220617A1 (en) 2008-09-04
US8236959B2 (en) 2012-08-07

Similar Documents

Publication Publication Date Title
EP2132179B1 (en) Process for preparing isomers of carmoterol
CN1107678C (zh) 高亲脂性喜树碱衍生物，其制备方法及其用途
JP5064214B2 (ja) キノリン誘導体のエナンチオ選択的製造
US20080194609A1 (en) Chemical Compound and Its Use
WO2008059223A2 (en) Process for the synthesis of moxifloxacin hydrochloride
EP1599450A1 (en) Process for preparing 5-"(r)-2-(5,6-diethyl-indian-2-ylamin o)-1-hydroxy-ethyl!-8-hydroxy-(1h)-quinolin-2-one salt, useful as an adrenoceptor agonist
US20120142728A1 (en) Chemical compound and its use
US20050215585A1 (en) Method of making 7-(4-bromobutoxy)-3,4-dihydrocarbostyril
JP2009510063A (ja) 特定のトリフルオロメチル置換アルコール類の立体選択的合成
US20170224713A1 (en) Heterocyclic compounds for treating or preventing disorers caused by reduced neurotransmission of serotonin, norephnephrine or dopamine
JP2007530652A (ja) 化学物質、調製方法、及び、新規結晶形態
EP2195295B1 (en) Method for the preparation of montelukast acid in ionic liquid medium
WO2008083551A1 (fr) Oxyphényl quinolines à substitution 4, composés intermédiaires, procédés d'élaboration et utilisations
CN1305995A (zh) 制备1,4－二氢吡啶化合物的方法
KR101404263B1 (ko) 8-히드록시-5-[(1ｒ)-1-히드록시-2-[[(1ｒ)-2-(4-메톡시페닐)-1-메틸에틸]아미노]에틸]-2(1ｈ)-퀴놀리논 모노하이드로클로라이드의 제조방법
WO2008077305A1 (fr) Composés de quinoléine, intermédiaires, procédés de préparation et utilisations de ceux-ci
US20100197910A1 (en) Process for preparation of prulifloxacin using novel intermediates
EP2081907B1 (en) Aryl piperazine derivatives useful for the treatment of neuropsychiatry disorders
JPWO2014051077A1 (ja) 高純度の含窒素複素環化合物の製造方法
US20110059019A1 (en) Novel aryl piperazine derivatives useful as modulators of dopamine and serotonin receptors
CN102442997B (zh) 一类喹啉衍生物、其制备方法、中间体及其应用
CN101146773A (zh) 用作抗炎药的6,7,8,9-四氢-5-氨基-5h-苯并环庚烯-6-醇衍生物及相关化合物
JP3022908B2 (ja) ８−ヒドロキシキノロンカルボン酸エステル類の製法
EP2487157A1 (en) Enantioselective synthesis method of 4-aminoalcoholquinoline derivatives and the use
JP2001181281A (ja) 抗菌剤として有用なキノロン誘導体

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20090925

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

17Q First examination report despatched

Effective date: 20100406

DAX Request for extension of the european patent (deleted)
GRAC Information related to communication of intention to grant a patent modified

Free format text: ORIGINAL CODE: EPIDOSCIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

Ref country code: AT

Ref legal event code: REF

Ref document number: 569692

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120815

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602008017790

Country of ref document: DE

Effective date: 20121004

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20120808

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 569692

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120808

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

Effective date: 20120808

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121208

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121108

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121109

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121210

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121119

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20130510

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121108

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602008017790

Country of ref document: DE

Effective date: 20130510

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130228

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20130228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130228

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130228

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20131031

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602008017790

Country of ref document: DE

Effective date: 20130903

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130228

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130228

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130228

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130903

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120808

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20080228

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130228